The present invention relates to new aminoisoquinoline derivatives which can be orally administrated to exhibit a strong anticoagulant effect by inhibiting activated blood-coagulation factor X; anticoagulants containing them as active ingredients; and agents for preventing or treating diseases caused by thrombi or emboli. These diseases include, for example, cerebrovascular disorders such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic attack (TIA) and subarachnoidal hemorrhage (vasospasm); ischemic heart diseases such as acute and chronic myocardial infarction, unstable angina and coronary thrombolysis; pulmonary vascular disorders such as pulmonary infarction and pulmonary embolism; peripheral obliteration; deep vein thrombosis; generalized intravascular coagulation syndrome; thrombus formation after an artificial blood vessel-forming operation or artificial valve substitution; re-occlusion and re-stenosis after a coronary bypass-forming operation; re-occlusion and re-stenosis after reconstructive operation for the blood circulation such as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal coronary recanalization (PTCR); and thrombus formation in the course of the extracorporeal circulation.
As the habit of life is being westernized and people of advanced ages are increasing in Japan, thrombotic and embolismic patients such as those suffering from myocardial infarction, cerebral thrombosis and peripheral thrombosis are increasing in number year by year, and the treatment of patients with these diseases is becoming more and more important in the society. Anticoagulation treatment is included in the internal treatments for the remedy and prevention of thrombosis, like radiotherapy and antithrombocytic therapy.
Antithrombins were developed as thrombus-formation inhibitors in the prior art. However, it has been known that since thrombin not only controls the activation of fibrinogen to form fibrin, which is the last step of the coagulation reaction, but also deeply relates to the activation and coagulation of blood platelets, the inhibition of the action of thrombin causes a danger of causing hemorrhage. In addition, when antithrombins are orally administered, the bioavailability thereof is low. At present, no antithrombin which can be orally administered is available on the market.
Since the activated blood coagulation factor X is positioned at the juncture of an exogenous coagulation cascade reaction and an endogenous coagulation cascade reaction and in the upstream of thrombin, it is possible to inhibit the coagulation system more efficiently and specifically, than the thrombin inhibition, by inhibiting the factor X (THROMBOSIS RESEARCH, Vol. 19, pages 339 to 349; 1980).
The object of the present invention is to provide compounds having an excellent effect of inhibiting the effect of activated blood coagulation factor X.
Another object of the present invention is to provide compounds having an effect of specifically inhibiting the effect of activated blood coagulation factor X, which can be orally administered.
Still another object of the present invention is to provide a blood-coagulation inhibitor or an agent for preventing or treating thrombosis of embolism, which contains one of the above-described compounds.
After intensive investigations made under these circumstances, the inventors have found that specified new aminoisoquinoline derivatives have an excellent effect of inhibiting activated blood coagulation factor X and are usable for preventing and treating various diseases caused by thrombi and emboli. The present invention has been completed on the basis of this finding.
Namely, the present invention provides aminoisoquinoline derivatives of following general formula (1) or pharmaceutically acceptable salts thereof: 
In general formula (1), A represents an organic group of following formula (2) and Axe2x80x2 represents a hydrogen atom, or Axe2x80x2 represents an organic group of following formula (2) and A represents a hydrogen atom:
Vxe2x80x94Lxe2x80x94Yxe2x80x94xe2x80x83xe2x80x83(2) 
In formula (2), L represents an organic group of any of the following formulae (3) to (6): 
In above formulae (3), (4) and (6), W represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 4 to 10 carbon atoms, an aralkyl group having 5 to 12 carbon atoms or a carboxyalkylsulfonyl group having 2 to 4 carbon atoms.
W is, for example, hydrogen atom, methyl group or benzyl group.
One of D and Dxe2x80x2 in formula (4) represents a bond to Y in general formula (2) and the other represents a hydrogen atom.
In formula (3), X represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms which may have a substituent or a benzyl group which may have a substituent. The substituent is selected from among carboxyl group, alkoxycarbonyl groups having 2 to 10 carbon atoms, alkylsulfonyloxy groups having 1 to 6 carbon atoms, piperidyloxy group, iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 7 to 14 carbon atoms, piperidylalkyl groups having 6 to 8 carbon atoms, iminoalkylpiperidylalkyl groups having 7 to 11 carbon atoms, alkoxycarbonylpiperidylalkyl groups having 8 to 15 carbon atoms, pyrrolidyloxy group, iminoalkylpyrrolidyloxy groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidyloxy groups having 7 to 13 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, hydroxyl group, halogeno groups, indolyl group and alkyl groups having 1 to 5 carbon atoms.
In formula (3), X and W may be bonded together to form a ring and, in this case, xe2x80x94Wxe2x80x94Xxe2x80x94 represents an ethylene group, trimethylene group or tetramethylene group.
When L is an organic group of any of formulae (3) to (5), V represents a hydrogen atom, an alkanesulfonyl group having 1 to 6 carbon atoms, which may have a substituent, or a benzoyl, benzenesulfonyl, 2-naphthalenesulfonyl, cinnamoyl, piperidinecarbonyl, phenylacetyl, pyridinecarbonyl, thiophenecarbonyl, phenylthiocarbonyl or benzimidoyl group which may have a substituent. When L is an organic group of formula (6), V represents an aryl group having 4 to 10 carbon atoms, which may have a substituent.
When L is an organic group of any of formulae (3) to (6) and V has a substituent, the substituent is selected from among carboxyl group, alkoxycarbonyl groups having 2 to 7 carbon atoms, carbamoyl group, mono- or dialkylcarbamoyl groups having 2 to 7 carbon atoms, amidino group, mono- or dialkylamidino groups having 2 to 7 carbon atoms, trialkylamidino groups having 4 to 7 carbon atoms, acyl groups having 1 to 8 carbon atoms, halogeno groups, amino group, mono- or dialkylamino groups having 1 to 6 carbon atoms, arylamino groups having 4 to 6 carbon atoms, alkoxycarbonylamino groups having 2 to 7 carbon atoms, aminoalkyl groups having 1 to 3 carbon atoms, mono- or dialkylamino groups having 2 to 7 carbon atoms, N-alkyl-N-alkoxycarbonylaminoalkyl groups having 4 to 10 carbon atoms, piperidyloxy group, acylpiperidyloxy groups having 6 to 9 carbon toms, iminoalkylpiperidyloxy groups having 6 to 10 carbon atoms, alkoxycarbonylpiperidyloxy groups having 8 to 14 carbon atoms, pyrrolidyloxy group, iminoalkylpyrrolidyloxy groups having 5 to 9 carbon atoms, alkoxycarbonylpyrrolidyloxy groups having 7 to 13 carbon atoms, hydroxycarbonylalkyl groups having 2 to 7 carbon atoms, alkoxycarbonylalkyl groups having 3 to 8 carbon atoms, hydroxycarbonylalkenyl groups having 3 to 7 carbon atoms, alkoxycarbonylalkenyl groups having 4 to 8 carbon atoms, aryl groups having 4 to 10 carbon atoms, arylalkenyl groups having 6 to 12 carbon atoms, alkoxyl groups having 1 to 10 carbon atoms, nitro group, trifluoromethyl group, alkyl groups having 3 to 8 carbon atoms, arylsulfonyl groups having 4 to 10 carbon atoms, arylalkyl groups having 5 to 12 carbon atoms, piperazinecarbonyl group, iminoalkylpiperazinecarbonyl groups having 7 to 10 carbon atoms, piperazinesulfonyl group, iminoalkylpiperazinesulfonyl groups having 6 to 9 carbon atoms, piperidylalkyl groups having 6 to 9 carbon atoms, iminoalkylpiperidylalkyl groups having 8 to 12 carbon atoms, piperididenealkyl groups having 6 to 9 carbon atoms, iminoalkylpiperidinealkyl groups having 8 to 12 carbon atoms, guanidino group, phosphono group, dialkoxyphosphoryl groups having 2 to 9 carbon atoms, monoalkoxyhydroxyphosphoryl groups having 1 to 4 carbon atoms and dialkylguadinino groups having 3 to 5 carbon atoms.
In formula (2), Y represents a group of any of the following formulae (7) to (13): 
In formulae (7) and (8), n represents an integer of 1 or 2. In formula (13), R1 represents a hydrogen atom, a hydroxycarbonylalkyl group having 2 to 7 carbon atoms, an alkoxycarbonylalkyl group having 3 to 8 carbon atoms or a hydroxycarbonylalkenyl group having 3 to 7 carbon atoms.
Z represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogeno group, an amino group or a group of any of following formulae (14) to (19): 
in formulae (14) and (17) to (19), n represents an integer of 0 to 3. In formula (14), R2 represents a hydroxyl group, a carboxyl group, an amino group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an aryl group having 4 to 10 carbon atoms, an alkoxyl group having 1 to 3 carbon atoms or an aralkyl group having 5 to 12 carbon atoms. In formula (15), R3 represents a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms, an aryl group having 4 to 10 carbon atoms, an alkoxyl group having 1 to 3 carbon atoms or an aralkyl group having 5 to 12 carbon atoms; R4 represents a hydrogen atom, an alkoxycarbonylamino group having 2 to 7 carbon atoms or an alkylcarbonylamino group having 2 to 7 carbon atoms. In formula (16), R5 represents a hydroxyl group, an amino group, an aryl group having 4 to 10 carbon atoms, an alkoxyl group having 1 to 3 carbon atoms or an aralkyl group having 5 to 12 carbon atoms. In formulae (17) to (19), R6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
The present invention also relates to aminoisoquinoline derivatives of following general formula (20), which have an effect of inhibiting the effect of activated blood coagulation factor X, and pharmaceutically acceptable salts of them. 
wherein one of B and Bxe2x80x2 represents an oil-soluble organic group and the other represents a hydrogen atom.
The present invention also provides a medicinal composition containing any of the above-described aminoisoquinoline derivatives and salts thereof as the active ingredient.
Further, the present invention provides an anticoagulant containing any of the above-described aminoisoquinoline derivatives and salts thereof as the active ingredient, or an agent for preventing or treating thrombi or emboli.